Resistance of tumor interstitial pressure to the penetration of intraperitoneally delivered antibodies into metastatic ovarian tumors.

PURPOSE: Despite evidence that regional chemotherapy improves the treatment of metastatic peritoneal ovarian carcinoma, monoclonal antibodies have not shown significant success in i.p. delivery. The present study was designed to address the hypothesis that convective penetration of macromolecular antineoplastic agents depends on a positive pressure difference between the i.p. therapeutic solution and the tumor. EXPERIMENTAL DESIGN: Nude rats with human ovarian xenografts implanted in the abdominal wall were used in experiments to facilitate in vivo measurement of tumor pressure and the treatment of the tumor with i.p. solutions at high pressures. Penetration of (125)I-labeled trastuzumab was measured with quantitative autoradiography. RESULTS: Tumor pressure profiles showed peak pressures of 32 mm Hg with mean pressures (+/- SD, mm Hg) in 12 SKOV3 tumors of 9.7 +/- 8.3 and in 15 OVCAR3 tumors of 12.5 +/- 7.0. I.p. therapeutic dwells at 6 to 8 mm Hg (maximum feasible pressure) showed significantly less penetration of trastuzumab than in adjacent normal muscle. To establish a driving force for convection into the tumor, various maneuvers were attempted to reduce tumor pressure, including treatment with taxanes or prostaglandin E(1), elimination of tumor circulation, and removal of the tumor capsule. Tumor decapsulation decreased the pressure to zero but did not enhance the penetration of antibody. Binding to specific trastuzumab receptors on each tumor was shown to be not a significant barrier to antibody penetration. CONCLUSIONS: The results only partially support our hypothesis and imply that the microenvironment of the tumor is in itself a major barrier to delivery of charged macromolecules.     

A Longitudinal Cohort Study of Youth Mental Health and Substance use Before and During the COVID-19 Pandemic in Ontario,Canada: An Exploratory Analysis

BackgroundYouth mental health appears to have been negatively impacted by the COVID-19 pandemic. The impact on substance use is less clear, as is the impact on subgroups of youth, including those with pre-existing mental health or substance use challenges.ObjectiveThis hypothesis-generating study examines the longitudinal evolution of youth mental health and substance use from before the COVID-19 pandemic to over one year into the pandemic among youth with pre-existing mental health or substance use challenges.MethodA total of 168 youth aged 14–24 participated. Participants provided sociodemographic data, as well as internalizing disorder, externalizing disorder, and substance use data prior to the pandemic’s onset, then every two months between April 2020–2021. Linear mixed models and Generalized Estimating Equations were used to analyze the effect of time on mental health and substance use. Exploratory analyses were conducted to examine interactions with sociodemographic and clinical characteristics.ResultsThere was no change in internalizing or externalizing disorder scores from prior to the pandemic to any point throughout the first year of the pandemic. Substance use scores during the pandemic declined compared to pre-pandemic scores. Exploratory analyses suggest that students appear to have experienced more mental health repercussions than non-students; other sociodemographic and clinical characteristics did not appear to be associated with mental health or substance use trajectories.ConclusionsWhile mental health remained stable and substance use declined from before the COVID-19 pandemic to during the pandemic among youth with pre-existing mental health challenges, some youth experienced greater challenges than others. Longitudinal monitoring among various population subgroups is crucial to identifying higher risk populations. This information is needed to provide empirical evidence to inform future research directions.     

The fate of isoprene inhaled by rats: comparison to butadiene

Isoprene (2-methyl-1,3-butadiene), a volatile monomer occurring in the natural environment and used in the manufacture of elastomers, is a close chemical relative of the animal carcinogen 1,3-butadiene. To obtain toxicokinetic data for inhaled isoprene, male F344 rats were exposed in groups of 30 to 14C-labeled isoprene vapor at four concentrations from 8 to 8200 ppm. The percentage of the inhaled isoprene that was metabolized decreased with increasing exposure concentration. The percentage of the total metabolites (that is, non-isoprene-retained 14C) excreted in urine and feces or expired was determined as a function of vapor concentration. About 75% of the total metabolites was excreted in urine. This was independent of inhaled isoprene concentration. After exposure to 8200 ppm, a larger percentage of the metabolites was excreted in feces than after exposure to lower concentrations. Using vacuum line techniques, blood metabolite concentrations were determined as functions of both vapor concentration and exposure duration. At one exposure concentration (1480 ppm) metabolites were measured in the nose, lungs, liver, kidney, and fat, as well as in blood. A mutagenic metabolite, isoprene diepoxide, was tentatively identified in all tissues examined. Between 0.0018 and 0.031% of the inhaled 14C label was tentatively identified as this metabolite in blood. The relative amount of the metabolites present in blood was highest for low concentrations of inhaled isoprene and for shorter exposure durations. Body fat appeared to be a reservoir for both isoprene metabolites and isoprene itself. The appearance of metabolites in the respiratory tract after short exposure durations together with low blood concentrations of isoprene indicated that substantial metabolism of inhaled isoprene in the respiratory tract may occur.